1. Field of the Invention
The present invention relates to the production of biocompatible magnetic nanoparticles which produce a large amount of heat when exposed to an alternating magnetic field. The produced heat can be used e.g., for therapeutic purposes, in particular for combating cancer.
2. Description of the Relevant Art
Magnetic nanoparticles can convert the energy of a magnetic field into heat in various ways. Besides the heating through so-called hysteresis losses nanoparticles can generate heat through relaxation (Néel and Brown relaxation, respectively). The amount of the produced thermal energy depends on the magnetic field strength (amplitude) and the frequency of the alternating field. The efficiency of the heat production can, at defined strength and frequency of the magnetic field, be estimated by the so-called SAR (specific absorption rate) or SLP (specific power loss) values. SAR values of a substance are normalized to the mass (in grams) used for the measuring and are expressed in the unit [W/g]. However, the SAR value of a magnetic substance depends yet on other factors, such as the particle size and the particle form, the anisotropy and the metal content of the substance. The SAR is preferably determined according to a method developed by Jordan et al. [International Journal of Hyperthermia, 1993, Vol. 9, No. 1, 51-68] at a frequency of 100 kHz and a field strength of up to 18 kA/m. Here, the SAR value is indicated by a normalization on the iron content of the substance in mW/mg Fe.
Biocompatible magnetic nanoparticles are frequently produced by a so-called precipitation process. This is described by many examples in literature [e.g. DE 196 14 136 A1]. Since these particles are produced in aqueous solution, they can be functionalized without problems and usually possess a good biocompatibility. The particles produced this way show, however, relatively low SAR values and can therefore not meet the innovative requirements of this patent.
Magnetic nanoparticles can also be produced by so-called magnetotactic bacteria [WO 98/40049]. The nanoparticles produced this way have a higher SAR. However, the production process is very complex and expensive. In addition the particles sediment relatively fast, thereby strongly limiting the possible applications.
It is known for years that thermal decomposition of metal complexes in organic solvents results in the formation of colloids or nanoparticles [e.g. Smith et al., J. Phys. Chem. 1980, 84, 1621-1629]. Monodisperse particles of different sizes can be produced by the method published by Pen et al. [US 2006/0211152 A1] and Hyeon et al. [WO 2006/057533 A1]. However, the particles produced by this method are dispersible in organic solvents only and therefore not biocompatible. Furthermore, the SAR values of the particles produced by this method are low. The dispersion of such (hydrophobic) particles in water can be principally achieved by a modification of the shell [e.g. Wang et al, Nano Lett., 2003, 3(11), 1555-1559 or De Palma et al., Chem. Mater, 2007, 19, 1821-1831]. These methods are based on the direct exchange of hydrophobic ligands through hydrophilic ligands. These coating methods result in only a thin (monolayer) coating which does not meet the requirement of a stable biocompatible coating. Furthermore, the colloidal stability of the particles is limited, so that the particles cannot be coated with this method. Further, only highly diluted dispersions of the particles can be coated. Thus, no satisfying technical solution for the dispersion of the particles exists on industrial scale. Further, the substances or solvents used for the dispersion usually possess a high toxicity, thus limiting the biocompatibility.
Biocompatible iron oxide nanoparticles can also be obtained by a coating with silanes according to DE 196 14 136 A1, however, this method is applicable only when the particles are already dispersed in water, whereas hydrophobic particles cannot be readily coated with silanes or silica.